tbuckley/cabot-search huggingface dataset:
P719: EFFICACY AND SAFETY OF BOSUTINIB IN LATER-LINE PATIENTS WITH CHRONIC MYELOID LEUKEMIA: A SUB-ANALYSIS FROM THE PHASE 4 BYOND TRIAL
Authors: C. Gambacorti-Passerini, T. H. Brümmendorf, T. Ernst, E. Leip, S. Purcell, A. Viqueira, F. J. Giles, G. Rosti, A. Hochhaus
Journal: HemaSphere (2022)

Background: Bosutinib is approved for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant or intolerant to prior therapy and newly diagnosed patients in chronic phase. The efficacy and safety of bosutinib in patients with CML resistant or intolerant to prior tyrosine kinase inhibitors (TKIs) was evaluated in the phase 4 BYOND trial (NCT02228382; Gambacorti-Passerini et al, Blood, 2021). Aims: The efficacy and safety of bosutinib in resistant and intolerant patients with CML treated with 2 (3L) and 3 (4L) prior TKIs was characterized. Methods: The BYOND trial included 163 patients with CML resistant or intolerant to prior TKIs. A sub-analysis of 48 patients treated with 2 (3L) and 3 (4L) prior TKIs, categorized by resistance or intolerance to the last received TKI, was performed. This sub-analysis is based on the final November 23, 2020 database lock. Results: There were 18 and 30 patients resistant or intolerant to the last received TKI who entered the study without complete cytogenetic response (CCyR) or major molecular response (MMR), respectively. Median (range) treatment duration was 10.6 months (1.6–48.5) vs 28.3 months (0.2–48.6) and median (range) dose intensity was 447.1 mg/d (131.3–520.4) vs 288.8 mg/d (79.7–500.0) for resistant vs intolerant patients. Prior TKIs included imatinib (88.9% vs 100.0%), dasatinib (88.9% vs 83.3%), and nilotinib (66.7% vs 63.3%) for resistant vs intolerant patients. Overall, 61.1% vs 66.7% of resistant vs intolerant patients discontinued bosutinib, mostly commonly due to adverse events (AEs) in 27.8% vs 16.7% patients; 16.7% vs 6.7% discontinued bosutinib due to insufficient clinical response. Rates of CCyR and MMR are shown in the Table. Among responders (resistant vs intolerant patients), median (range) time to CCyR was 5.1 months (2.8–8.8) vs 3.0 months (2.7–6.1); median (range) time to MMR was 5.8 months (2.8–9.4) vs 3.2 months (2.8–9.3). In resistant vs intolerant patients, any grade treatment-emergent AEs (TEAEs) were reported by 100.0% vs 96.7% patients; grade 3/4 TEAEs were reported by 72.2% vs 83.3% patients. Grade 3/4 TEAEs >10% in resistant patients were thrombocytopenia (22.2%) and neutropenia (11.1%), and in intolerant patients were increased alanine aminotransferase (26.7%), diarrhea (23.3%), pleural effusion (13.3%), and rash (13.3%). Image:Summary/Conclusion: This sub-analysis of resistant and intolerant patients without baseline CCyR or MMR shows bosutinib was active in heavily pretreated patients with resistance or intolerance to the last received TKI. Despite a difference between resistant and intolerant patients with CML, efficacy outcomes, though lower than the overall BYOND population, are encouraging, and safety was generally consistent with previous reports.
P663: HEALTH-RELATED QUALITY OF LIFE OUTCOMES ASSOCIATED WITH ZANUBRUTINIB VS IBRUTINIB MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY (RR) CLL/SLL: RESULTS FROM THE RANDOMIZED PHASE 3 ALPINE TRIAL
Authors: P. Hillmen, J. Brown, N. Lamanna, S. O’Brien, C. Tam, L. Qiu, K. Yang, G. Barnes, K. Wu, T. Salmi, B. Eichhorst
Journal: HemaSphere (2022)

Background: In the phase 3 ALPINE trial (BGB-3111-305; NCT03734016), efficacy and safety of zanubrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor (BTKi), were compared with the first-generation BTKi, ibrutinib, in adult patients with RR chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aims: This abstract, based on the interim analysis of the ALPINE trial, describes the effects of zanubrutinib monotherapy and ibrutinib monotherapy on the health-related quality of life (HRQoL). Methods: Health-related quality of life was examined by patient-reported outcomes (PROs) measures assessed by EORTC QLQ-C30 and EQ-5D-5L at baseline, Cycle 1, and then every 3rd cycle until end of treatment. Key PRO endpoints included global health status (GHS), physical and role functions, and fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis on all the scales was conducted as was a mixed model repeated-measure (MMRM) analysis of the longitudinal QLQ-C30 data. Data presented are from key cycles (7 and 13), corresponding to 6 and 12 months of treatment, respectively. Results: In the intent-to-treat population (N=652; zanubrutinib, n=327; ibrutinib, n=325), adjusted completion rates were high (>85%) in both arms at Cycles 7 and 13. On the QLQ-C30, estimated mean treatment differences and 95% CI in key PRO endpoints demonstrated treatment differences, in favor of zanubrutinib, in GHS, physical functioning, and fatigue in Cycle 7, and diarrhea in Cycle 13 (Table). Mean change from baseline (SD) in EQ-5D-5L VAS showed consistently more improvement with zanubrutinib compared with ibrutinib at both Cycle 7 (8.4 [18.2] vs 4.0 [16.6]) and Cycle 13 (6.8 [18.8] vs 5.2 [17.5]). Image:Summary/Conclusion: In the ALPINE trial, patients with RR CLL/SLL who received zanubrutinib monotherapy reported improvements in key HRQoL endpoints compared with patients who received ibrutinib monotherapy.
P808: CONGENITAL NEUTROPENIA PREVALENCE AMONG POLISH CHILDREN – SUMMARY OF A NATIONWIDE GENETIC SCREENING CAMPAIGN
Authors: K. Bąbol-Pokora, W. Dobrewa, M. Bielska, J. Madzio, S. Janczar, W. Młynarski
Journal: HemaSphere (2022)

Background: Severe congenital neutropenia (SCN) is a heterogenous group of rare primary immunodeficiency disorders, characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent gingivitis, mouth and rectal ulcerations, and often life-threatening bacterial infections. They are also predisposed to myelodysplastic syndromes or acute myeloid leukemias. Nine types of severe congenital neutropenia have been distinguished so far with the most frequent pathogenetic defects in the ELANE gene. This study explores the distribution and mutation spectrum of disease-causing genetic variants associated with congenital neutropenia in the Polish pediatric cohort and the observed ten-fold increase in the referral rate following a nationwide information campaign. Aims: The aim of this study was to estimate prevalence of congenital and autoimmune neutropenia among Polish children and to improve the efficiency of recruiting patients with suspected SCN by launching the FIX-NET project with a nationwide advertising campaign. Methods: Molecular analyses were performed either by direct Sanger sequencing (78 patients recruited in 2008-2015) or by Targeted NGS (201 patients recruited in 2016-2021) using Illumina platform, focused on the 54 genes related to SCN and neutropenia associated syndromes. Overall 279 neutropenic patients were enrolled in the studies and written informed consent has been given. The following results describe the largest cohort of genetic variation associated with SCN in Poland. Results: We identified pathogenic changes in genes associated to severe congenital neutropenia or related syndromes among 66 patients, most of which were variants in the ELANE gene (44%). There were a number of patients with pathogenic changes in CXCR4 (12%) and SBDS (11%) genes, and also in the recently described dominant SCN-related genes – SRP54 (8%) and CLPB (5%). Novel mutations accounted for 30% of all reported variants. In addition among 32 patients we found changes in genes that cause neutrophil dysfunctions or may lead to autoimmune neutropenia, such as AIRE, FAS, or CTLA4. Summary/Conclusion: Our study shows the prevalence of congenital neutropenia in Poland in the largest pediatric neutropenic cohort described so far. It indicates that since the introduction of NGS to the diagnosis of primary and secondary neutropenia, more genetic changes have been detected, however, the greatest impact on increasing awareness among doctors, and thus improving the effectiveness of recruitment had the nationwide information campaign.
P1443: AUTOLOGOUS NK CELLS AS CONSOLIDATION AFTER FRONT-LINE STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA: A LONG-TERM FOLLOW-UP
Authors: J. Lund, H. Nahi, S. Meinke, P.-H. Holmqvist, H.-G. Ljunggren, J. Aschan, E. Alici
Journal: HemaSphere (2022)

Background: Immunotherapies have shown great anti-tumour effect in a variety of malignancies. In multiple myeloma (MM) antibodies, including bispecific T cell engagers, antibody-drug conjugates, and more recently, CAR T cells have reported exciting clinical results and many of them have been incorporated in the treatment armamentarium. Less is reported for NK cells, in particular autologous NK cells. Initial results from our first-in-human trial ACP-001 with autologous NK cells given as consolidation after front-line autologous stem cell transplantation (ASCT) were recently reported (Nahi et al., 2022, Cell Reports Medicine 3, 100508 February 15, 2022). It showed that the concept was feasible with good safety, including no SAEs, and promising efficacy. We here report the long-term clinical follow-up. Aims: The aim of this report was to investigate long-term safety, disease progression, second-line therapy and survival after autologous NK cell treatment. Methods: This first-in-human trial included six patients with newly diagnosed MM eligible for ASCT at the Karolinska University Hospital Huddinge in Sweden. After standard induction treatment (bortezomib, cyclophosphamide and dexamethasone (VCD) at the time) and ASCT with melphalan 200 mg/m2 (MEL200) the patients received three escalating doses of autologous activated and expanded NK cells. Clinical data on long-term safety, disease progression, second-line therapy and survival were captured from the patients’ electronical charts. Results: No subject were lost to follow-up or had withdrawn from the study. With a median follow-up from study inclusion of 6.9 (6.1-7.2) yrs, and 6.2 (5.4-6.7) yrs from the first NK cell infusion, there are no new reported AE related to the NK cell infusions. All six patients are alive with one subject still in first remission 6.8 yrs after inclusion. Five patients had disease progression 13-51 months after study inclusion and four of them underwent reinduction (VRD (n=2), KRD (n=1), KRD+dara (n=1)) followed by a second ASCT with MEL200. The fifth patient progressed within the first yr after ASCT and received VRD+dara. All five patients responded to second line treatment with PR (n=2), VGPR (n=2) and MRD negative (n=1) but subsequently progressed with a PFS2 ranging from 11.5 to 26.3 months. Summary/Conclusion: This long-term follow-up confirms the safety and feasibility of autologous NK cell therapy as consolidation after front line ASCT in MM. Autologous NK cell treatment in first line did not negatively impact the possibility to administer, or the outcome, of later treatments which is important with all new treatment options for patients with advanced MM.
P608: DISTINCT P53 PHOSPHORYLATION PATTERNS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS ARE REFLECTED IN CIRCUMJACENT PATHWAYS’ ACTIVATION UPON DNA DAMAGE
Authors: M. Pesova, V. Mancikova, R. Helma, S. Pavlova, V. Hejret, P. Taus, J. Hynst, K. Plevova, J. Kotaskova, J. Malcikova, S. Pospisilova
Journal: HemaSphere (2022)

Background: Presence of defects in the TP53 gene represents a clinically relevant biomarker in chronic lymphocytic leukemia (CLL). Besides gene mutations and deletions, the functionality of p53 protein can be disrupted by other mechanisms, such as aberrant phosphorylation. Aims: To uncover how p53 phosphorylations affect its functions in CLL cells. Methods: P53 phospho-patterns were analyzed in 71 TP53-intact primary CLL samples using Zn2+-Phos-tag™ SDS-PAGE after induction of p53 protein by DNA damage (fludarabine and doxorubicin treatments). Differences in gene expression were studied using RNA sequencing and compared to CLL cells carrying the mutated TP53 gene. The ability of p53 to activate transcription of its target genes (BAX, BBC3, CDKN1A, GADD45A) was assessed by qPCR. The presence of gene mutations was analyzed using a targeted NGS panel. Results: While fludarabine induced a consistent phospho-pattern, two distinct p53 phosphorylation profiles were identified upon doxorubicin treatment. Profile I featured heavily phosphorylated p53 protein, while only low phosphorylation occurred in profile II. On the transcriptomic level, samples from the profile II were less capable of activating p53 target genes upon doxorubicin treatment, thus resembling TP53-mutant cells, whereas proper p53 signaling was triggered in profile I. Consistently, induction of the studied downstream effector genes CDKN1A, BAX, BBC3 and GADD45 after doxorubicin treatment was lower in profile II than in profile I samples but still higher than in TP53 mutants. The differences between the two phoshoprofiles were also observed in untreated cells: the expression of miR-34 in profile II showed an intermediate pattern between profile I and TP53-mutant cells. Furthermore, profile II samples had significantly higher basal p53 protein levels than profile I samples, where p53 was generally detectable only upon DNA damage. The PROGENy analysis of the basal activity of selected cancer-related pathways in untreated cells pointed to the different regulation of the hypoxic pathway: the activity of hypoxic pathway in profile II samples was in between high levels found in TP53 mutants and low levels in profile I. Finally, we have found ATM locus/gene defects more frequently in profile II. Summary/Conclusion: Our study suggests that wt-TP53 CLL cells with less phosphorylated p53 show TP53-mutant-like behavior after DNA damage. Hypophosphorylation of p53 protein and the corresponding lower ability to respond to DNA damage are linked to ATM locus defects and to the higher basal activity of the hypoxia pathway. The project was supported by GACR 19-15737S, MZCR-RVO 65269705, MUNI/A/1330/2021 and AZV NU21-08-00237.
P358: COMPREHENSIVE DIAGNOSTICS OF ACUTE LYMPHOBLASTIC LEUKEMIA BY WHOLE TRANSCRIPTOME RNA SEQUENCING
Authors: J. Li
Journal: HemaSphere (2022)

Background: Acute lymphoblastic leukemia (ALL) has genetic heterogeneity, which is helpful to clinical diagnosis, prognosis stratification and treatment guidance. Gene aberrations are structurally diverse and are currently analyzed by different assays. Aims: This study aims to establish a single and comprehensive platform for ALL diagnosis by whole transcriptome RNA sequencing (WTRS), which can detect fusion, mutations and expression. Methods: We analyzed the data of 70 ALL patients by WTRS. Results: We found that the fusion coincidence rate of WTRS was 100% (19 / 19) comparing with quantitative real-time polymerase chain reaction (qPCR). At the same time, six rare fusion forms were detected, which increased the diagnosis rate of fusion gene from 27% (19 / 70) to 36% (25 / 70). The expression of CRLF2 gene in 5 cases was consistent with that of qPCR. Seven cases with IKZF1 gene skipping identified by qPCR were consistent with the results of WTRS, and a rare IKZF1 deletion subtype was detected. Of the 51 genes associated with ALL, 100% (103/103) gene mutation at the RNA level by WRTS is consistent with the results at the DNA level by targeted DNA sequencing (except 3 splice site mutations and 4 mutations with poor coverage). Summary/Conclusion: In conclusion, the standardization of experimental operation and improvement of biological information pipline of WRTS are very important factors in its use in standard diagnostic procedures. WRTS has the potential to provide accurate comprehensive diagnostic information for clinic and further improve the ALL diagnostic rate.
P1302: INTEGRATION OF ROUTINE RNA AND WHOLE-EXOME SEQUENCING AND FLOW CYTOMETRY IMPROVES THE DIAGNOSTIC WORKUP OF PEDIATRIC LYMPHOMAS
Authors: L. Westera, M. Scheijde-Vermeulen, L. Kester, B. Tops, F. Meyer-Wentrup
Journal: HemaSphere (2022)

Background: Lymphomas are traditionally diagnosed by histology and immunohistochemistry, complemented by molecular methods like fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) to detect the genetic abnormalities that define certain malignancies. Aims: To improve both diagnostic accuracy and efficiency, we aimed to implement RNA sequencing (RNAseq) and Whole Exome Sequencing (WES) and flow cytometry into the routine diagnostic workup of pediatric lymph node biopsies. Methods: Within a year we analyzed 122 lymph node biopsies of all 110 children referred to our new Dutch National Pediatric Cancer Center because of suspected malignant lymphoma, using a standardized workflow combining histology and immunohistochemistry, flow cytometry, and next-generation sequencing technologies. Results: Flow cytometry was performed with fresh tissue directly after biopsy in 83% of specimens (101/122) and allowed rapid diagnosis of mature and immature T- and B-cell non-Hodgkin lymphomas (NHL), enabling early treatment initiation in ill patients. RNAseq was performed on all biopsies of NHL and in a subset of Hodgkin lymphoma (HL) samples. RNAseq detected the vast majority of translocations found by traditional methods. In some cases IgH::MYC translocations were not detected by RNAseq, but for these cases expression analysis showed high MYC expression indicative of the underlying IgH::MYC translocation. In addition, both RNAseq and WES identified additional genetic abnormalities not found by conventional approaches. In several cases WES and/or RNA sequencing resolved remaining diagnostic uncertainty. Machine learning analysis of the RNA sequencing data allowed correct lymphoma subtype classification in >90% of NHL. Classification of HL was less accurate due to the low tumor content of HL. Summary/Conclusion: The successful integration of histology and immunohistochemistry, flow cytometry, and next-generation sequencing technologies into one standardized workflow depends on close multidisciplinary collaboration of different clinical and laboratory specialists, which has been greatly facilitated by the recent centralization of diagnostics and care for pediatric cancer patients. We highlight a few cases that are exemplary of how the synergy between different diagnostic techniques and specialists can improve diagnostic accuracy and speed and thus benefit patients.
Analysis of Variation Between Diagnosis at Admission vs Discharge and Clinical Outcomes Among Adults With Possible Bacteremia
Authors: Emma Dregmans, Anna G. Kaal, Soufian Meziyerh, Nikki E. Kolfschoten, Maarten O. van Aken, Emile F. Schippers, Ewout W. Steyerberg, Cees van Nieuwkoop
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Misdiagnosis of infection is among the most commonly made diagnostic errors and is associated with increased morbidity and mortality. Little is known about how often misdiagnosed site of infection occurs and its association with clinical outcomes. <h3>Objectives</h3> To evaluate the discrepancy between admission and discharge site of infection diagnoses among patients with suspected bacteremia, to explore factors associated with discrepant diagnoses, and to evaluate the association with clinical outcomes. <h3>Design, Setting, and Participants</h3> This cohort study used electronic records of 1477 adult patients who were admitted to the hospital for suspected bacteremia from April 1, 2019, to May 31, 2020, and who had blood cultures taken at the emergency department at Haga Teaching Hospital, The Hague, the Netherlands. Suspected infection sites were classified into 8 categories at admission and discharge. Misdiagnosed site was defined as a discrepancy between the suspected site of infection at admission and at discharge. <h3>Main Outcomes and Measures</h3> Clinical outcomes were 30-day mortality, intensive care unit admission, length of hospital stay, and antibiotic use, analyzed with logistic and linear regression. Risk factors for misdiagnosed site were determined using regression analysis. <h3>Results</h3> A total of 1477 patients (820 [55.5%] male; median [IQR] age, 68 [56-78] years) were analyzed. The rate of misdiagnosed site of infection was 11.6% (171 of 1477); 3.1% of all patients (46 of 1477) ultimately had no infection. No association was found between misdiagnosis and 30-day mortality (adjusted odds ratio [aOR], 0.8; 95% CI, 0.3-1.9;<i>P</i> = .60), intensive care unit admission (aOR, 1.3; 95% CI, 0.6-3.0;<i>P</i> = .54), and hospital length of stay (adjusted increase of stay, 15.5%; 95% CI, −3.1% to 37.7%;<i>P</i> = .11). Misdiagnosed site was associated with receiving broad-spectrum antibiotics (aOR, 4.0; 95% CI, 1.8-8.8;<i>P</i> &lt; .001). Older age, dementia, a positive urine sediment test result without urinary symptoms, and suspicion of an intravascular, central nervous system, or bone and joint infection were risk factors for misdiagnosed site of infection. <h3>Conclusions and Relevance</h3> In this cohort study, misdiagnosed site of infection occurred in 1 of 9 patients and was not associated with worse short-term clinical outcomes. Clinicians should be aware of risk factors associated with misdiagnosed site of infection and potential inappropriate antibiotic use.